Hepcidin: a key regulator of inflammation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE95162 | GEO | 2021/02/13
REPOSITORIES: GEO
Similar Datasets
Project description:Hepcidin is demonstrated to be the key iron regulatory hormone, produced by the liver. Here we show an unexpected role of hepcidin as a master initiator of the local and systemic inflammatory response. We found that hepcidin was highly expressed in the colon of two major idiopathic inflammatory bowel diseases : Crohn's disease (CD) and ulcerative colitis (UC). Thanks to the generation of intestinal specific hepcidin KO mice (Hepc{delta}int), we found in a DSS-induced colitis model that hepcidin mediated the induction of key inflammatory cytokines and was protective against intestinal injury. In a model of LPS-induced acute inflammation, intestinal hepcidin expression was increased through a TLR4 dependent pathway andwas required for intestinal neutrophil infiltration and inflammation. Strikingly, intestinal hepcidin was absolutely required for the systemic production of key inflammatory cytokines (IL-6, CXCL1, TNF-alpha ...) as well as for the setting of the hypoferremia of inflammation. In a sepsis model, Hepc{delta}int mice were protected against LPS-induced mortality. Mechanistically, we showed that hepcidin was a direct neutrophil chemoattractant and a proinflammatory molecule in macrophages through a Myd88 dependent pathway. Altogether, we demonstrated that Hepcidin is a key new essential component of the immune system and may be a promising target in many inflammatory diseases. We used microarrays to detail the global program of gene expression of BMDM treat with hepcidin for 1 hour.
2016-07-16 | E-GEOD-71073 | biostudies-arrayexpress
Project description:Hepcidin is demonstrated to be the key iron regulatory hormone, produced by the liver. Here we show an unexpected role of hepcidin as a master initiator of the local and systemic inflammatory response. We found that hepcidin was highly expressed in the colon of two major idiopathic inflammatory bowel diseases : Crohn's disease (CD) and ulcerative colitis (UC). Thanks to the generation of intestinal specific hepcidin KO mice (Hepc{delta}int), we found in a DSS-induced colitis model that hepcidin mediated the induction of key inflammatory cytokines and was protective against intestinal injury. In a model of LPS-induced acute inflammation, intestinal hepcidin expression was increased through a TLR4 dependent pathway andwas required for intestinal neutrophil infiltration and inflammation. Strikingly, intestinal hepcidin was absolutely required for the systemic production of key inflammatory cytokines (IL-6, CXCL1, TNF-alpha ...) as well as for the setting of the hypoferremia of inflammation. In a sepsis model, Hepc{delta}int mice were protected against LPS-induced mortality. Mechanistically, we showed that hepcidin was a direct neutrophil chemoattractant and a proinflammatory molecule in macrophages through a Myd88 dependent pathway. Altogether, we demonstrated that Hepcidin is a key new essential component of the immune system and may be a promising target in many inflammatory diseases.
2019-02-14 | GSE71073 | GEO
Project description:Liver iron overload can induce hepatic expression of hepcidin and regulates iron metabolism. However, the mechanism of iron regulating iron metabolism remains known. Intracellular labile iron represents the nonferritin-bound, redox-active iron which is transitory and serves as a crossroad of cell iron metabolism. The role of intracellular labile iron played in iron metabolism has largely been elucidated. Here we show that intracellular labile iron of hepatocytes has dual function in iron metabolism. It can induce hepatocytes expressing hepcidin via ER stress induced transcription factors on the one hand, on the other hand stimulate BMP2 and BMP6 expression of liver sinusoidal endothelial cells (LSECs) though TNFα secreted by hepatocytes to further regulate iron metabolism. Blockade of TNFα could dysregulate the iron metabolism during iron overload. Our findings reveal the important role of intracellular labile iron in iron metabolism and represent a novel way to modulate iron metabolism during iron overload.
2023-05-03 | GSE186655 | GEO
Project description:Intracellular labile iron is a key regulator of hepcidin expression and iron metabolism
| PRJNA774974 | ENA
Project description:Hepcidin, a peptide hormone that decreases intestinal iron absorption and macrophage iron release, is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. Endogenous stimulants of Hepcidin transcription include bone morphogenic protein 6 (BMP) and interleukin-6 (IL-6) via effects on Smad4 or Stat3, respectively. We conducted a small-scale chemical screen in zebrafish embryos to identify small molecules that modulate hepcidin expression. We found that treatment with the isoflavone genistein from 28−52 hours post-fertilization in zebrafish embryos enhanced Hepcidin transcript levels as assessed by whole mount in situ hybridization and quantitative realtime RT-PCR. Genistein’s stimulatory effect was conserved in human hepatocytes: genistein treatment of HepG2 cells increased both Hepcidin transcript levels and Hepcidin promoter activity. We found that genistein’s effect on Hepcidin expression did not depend on estrogen receptor signaling or increased cellular iron uptake, but was impaired by mutation of either the BMP response elements or the Stat3 binding site in the Hepcidin promoter. RNA-sequencing of transcripts from genistein-treated hepatocytes indicated that genistein upregulated 68% of the transcripts that were upregulated by BMP6, however genistein raised the levels of several transcripts involved in Stat3 signaling that were not upregulated by BMP6. Chromatin-immunoprecipitation and ELISA experiments revealed that genistein enhanced Stat3 binding to the Hepcidin promoter and increased phosphorylation of Stat3 in HepG2 cells. CONCLUSION: Genistein is the first small molecule experimental drug that stimulates Hepcidin expression in vivo and in vitro. These experiments demonstrate the feasibility of identifying and characterizing small molecules that increase Hepcidin expression. Genistein and other candidate molecules may subsequently be developed into new therapies for iron overload syndromes.
2015-08-13 | GSE40069 | GEO
Project description:Hepcidin, a peptide hormone that decreases intestinal iron absorption and macrophage iron release, is a potential drug target for patients with iron overload syndromes because its levels are inappropriately low in these individuals. Endogenous stimulants of Hepcidin transcription include bone morphogenic protein 6 (BMP) and interleukin-6 (IL-6) via effects on Smad4 or Stat3, respectively. We conducted a small-scale chemical screen in zebrafish embryos to identify small molecules that modulate hepcidin expression. We found that treatment with the isoflavone genistein from 28−52 hours post-fertilization in zebrafish embryos enhanced Hepcidin transcript levels as assessed by whole mount in situ hybridization and quantitative realtime RT-PCR. Genistein’s stimulatory effect was conserved in human hepatocytes: genistein treatment of HepG2 cells increased both Hepcidin transcript levels and Hepcidin promoter activity. We found that genistein’s effect on Hepcidin expression did not depend on estrogen receptor signaling or increased cellular iron uptake, but was impaired by mutation of either the BMP response elements or the Stat3 binding site in the Hepcidin promoter. RNA-sequencing of transcripts from genistein-treated hepatocytes indicated that genistein upregulated 68% of the transcripts that were upregulated by BMP6, however genistein raised the levels of several transcripts involved in Stat3 signaling that were not upregulated by BMP6. Chromatin-immunoprecipitation and ELISA experiments revealed that genistein enhanced Stat3 binding to the Hepcidin promoter and increased phosphorylation of Stat3 in HepG2 cells. CONCLUSION: Genistein is the first small molecule experimental drug that stimulates Hepcidin expression in vivo and in vitro. These experiments demonstrate the feasibility of identifying and characterizing small molecules that increase Hepcidin expression. Genistein and other candidate molecules may subsequently be developed into new therapies for iron overload syndromes. RNA-seq of HepG2 cells treated with DMSO 1%, BMP6 50 ng/ml, or genistein 10 micromolar. The numbers of biological replicates were 3, 2, and 3.
2015-08-13 | E-GEOD-40069 | biostudies-arrayexpress
Project description:Bleeding and altered iron distribution occur in multiple gastrointestinal diseases, but the significance or regulation of these changes remains unclear. Here we report that hepcidin, the master regulator of systemic iron homeostasis, is required for tissue repair in the intestine following experimental damage. This effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Rather, we identified that conventional dendritic cells (DCs) are a source of hepcidin that is induced by microbial stimulation, prominent in the inflamed intestine of humans, and essential for tissue repair. Mechanistically, DC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration, which regulated the microbiota and subsequently facilitated intestinal repair. Collectively, these results identify a novel pathway whereby DC-derived hepcidin promotes mucosal healing in the intestine via nutritional immunity.
2020-04-15 | GSE139371 | GEO
Project description:Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin (Hamp), a hepatic-derived hormone that controls iron mobilization through its molecular target, ferroportin (FPN), the only known mammalian iron exporter. Here, we took a transcriptomic approach to to compare the duodenal transcriptome during systemic iron demand to that of hepcidin-deficiency iron overload. Hampfl/fl (control) and AlbCreERT2;Hampfl/fl mice were placed on iron-replete and low-iron diets and were sacrificed two weeks following tamoxifen treatment. Duodenum RNA expression was compared across genotypes and across iron-replete and low iron diets.
2018-12-12 | E-MTAB-7329 | biostudies-arrayexpress
Project description:We used NGS sequencing of RNA (RNA-Seq) in livers of mice treated with a 3 week low iron (2-6 parts per million) diet, and treatment with either RGFP966 (an HDAC3 specific inhibitor) or vehicle. Our primary interest is in the role of HDAC3 in expression of the iron regulatory hormone hepcidin (Hamp1 in mice).
2017-06-29 | GSE100608 | GEO
Project description:Tmprss6 is the master inhibitor of hepcidin and its inactivation causes iron refractory iron deficiency anemia both in human and in mice. Mice with iron deficiency anemia (IDA)-low hepcidin show a pro-inflammatory response that is blunted in iron deficienct-high hepcidin Tmprss6 null mice. We investigated the transcriptional response associated with chronic hepcidin overexpression by comparing whole genome transcription profiling of the liver of Tmprss6 KO mice and IDA animals, irrespective of iron deficiency.
2013-10-09 | GSE46287 | GEO